The present invention relates to a stable and novel type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione (referred to as xe2x80x9cMCC-555xe2x80x9d in the specification), which is useful as an active ingredient of therapeutic medicaments for diabetes and a complication thereof, hyperlipidemia and a complication thereof and the like.
Diabetes is a complicated disease caused by hyperglycemia, and the disease is brought by deficiency of insulin action which reduces blood glucose. Diabetes can be classified into several types based on their pathologic state. Among them, those regarded as important are insulin dependent diabetes (type I diabetes) which requires supplement of insulin because of its deficiency, and non-insulin dependent diabetes (type II diabetes) where insulin fails to effect due to abnormalities of receptors, saccharide transporting carriers and the like, although sufficient amount of insulin is secreted.
In recent years, agents improving insulin resistance have been much interested which reduce blood glucose by improving insulin resistance in peripheral tissues that is a cause of non-insulin dependent diabetes.
Some of the inventors of the present invention achieved an invention relating to 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione, an agent for improving insulin resistance that has excellent hypoglycemic action and hypolipidemic action, and filed patent applications directed to the invention (the Japanese Patent Unexamined Publication (KOKAI) Nos. (Hei) 6-247945/1994 and (Hei) 10-139768/1998). The claims of the Japanese Patent Unexamined Publication (KOKAI) (Hei) 6-247945/1994 are directed to novel naphthalene derivatives including 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione and salts thereof having hypoglycemic and hypolipidemic action, and the claims of the Japanese Patent Unexamined Publication No. (Hei) 10-139768/1998 are directed to an industrial process of manufacture thereof.
The present invention is based on the discovery that a novel crystal form of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione is apparently superior to other crystal forms. The novel crystal form is herein referred to as xe2x80x9ctype A crystal,xe2x80x9d whereas the other crystal forms mentioned herein are referred to as xe2x80x9ctype B crystalxe2x80x9d, xe2x80x9ctype C crystal,xe2x80x9d and xe2x80x9ctype D crystalxe2x80x9d only for reasons of convenience. The type A crystal has a novel crystal form, and its excellent stability and a manufacturing process thereof have not been known to date. According to the method disclosed in the Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 6-247945/1994, 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione is recrystallized in the presence of a mixed solvent of ethyl acetate and hexane to obtain polymorphic forms of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione. As a product of the aforementioned method, the type D crystal or a mixture mainly composed of the type D crystal may be obtained depending on various factors such as heating temperature, an amount or a mixing ratio of the solvents and the like, and accordingly, the type A crystal cannot be obtained alone. According to the method of the Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 10-139768/1998, 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione is recrystallized in toluene as a solvent to obtain polymorphic forms of the compound. This method may most frequently yield a product comprising a mixture of the type A and type D crystals with a fluctuating content ratio depending on various factors such as heating temperature, a cooling rate, an amount of the solvent and the like. However, these patent documents are silent about the possibility of the polymorphism, and hence no information about the type A, B, C and D crystals are disclosed therein.
The present invention provides a crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione distinguishable from the known crystals, which is novel and excellent in stability, and has advantages in handling, storage, and manufacture of pharmaceutical preparation.
The present invention thus provides Type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione characterized to have characteristic absorption peaks (2xcex8) at 11.5xc2x0xc2x10.3xc2x0 in a powder X-ray diffraction pattern.
According to preferred embodiment of the present invention, there are provided the type A crystal of said compound characterized to have characteristic absorption peaks (2xcex8) at 11.5xc2x0xc2x10.3xc2x0 and 25.7xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern; The type A crystal of said compound characterized to have characteristic absorption peaks (2xcex8) at 22.4xc2x0xc2x10.5xc2x0 and 25.7xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern; The type A crystal of said compound characterized to have characteristic absorption peaks (2xcex8) at 11.5xc2x0xc2x10.3xc2x0 and 22.4xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern; The type A crystal of said compound characterized to have characteristic absorption peaks (2xcex8) at 11.5xc2x0xc2x10.3xc2x0, 17.0xc2x0xc2x10.3xc2x0, 17.7xc2x0xc2x10.2xc2x0, 22.4xc2x0xc2x10.5xc2x0 and 25.7xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern; and the type A crystal of said compound characterized to have characteristic absorption peaks (2xcex8) at 11.5xc2x0xc2x10.3xc2x0, 14.5xc2x0xc2x10.2xc2x0, 16.2xc2x0xc2x10.3xc2x0, 17.0xc2x0xc2x10.3xc2x0, 17.7xc2x0xc2x10.2xc2x0, 18.6xc2x0xc2x10.3xc2x0, 19.1xc2x0xc2x10.2xc2x0, 21.3xc2x0xc2x10.4xc2x0, 22.4xc2x0xc2x10.5xc2x0, 25.7xc2x0xc2x10.5xc2x0 and 28.3xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern.
The present invention also provides a method for preparing the aforementioned type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione, which comprises the step of heating and stirring 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}-methyl]-2,4-thiazolidinedione in an alcoholic solvent, and a pharmaceutical composition comprising the aforementioned type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides type B crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl-]-2,4-thiazolidinedione characterized to have characteristic diffraction peaks (2xcex8) at 10.5xc2x0xc2x10.5xc2x0, 18.4xc2x0xc2x10.5xc2x0, 20.9xc2x0xc2x10.5xc2x0, 23.0xc2x0xc2x10.5xc2x0, 26.7xc2x0xc2x10.5xc2x0 and 29.2xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern;
type C crystal of said compound characterized to have characteristic diffraction peaks (2xcex8) at 12.5xc2x0xc2x10.5xc2x0, 14.5xc2x0xc2x10.5xc2x0, 17.6xc2x0xc2x10.5xc2x0, 18.8xc2x0xc2x10.5xc2x0, 22.1xc2x0xc2x10.5xc2x0, 25.9xc2x0xc2x10.5xc2x0, 26.6xc2x0xc2x10.5xc2x0 and 28.3xc2x0xc2x10.5xc2x0 in a powder X-ray diffraction pattern; and
type D crystal of said compound characterized to have characteristic diffraction peaks (2xcex8) at 10.7xc2x0xc2x10.2xc2x0, 14.5xc2x0xc2x10.2xc2x0, 15.1xc2x0xc2x10.2xc2x0, 15.8xc2x0xc2x10.2xc2x0, 17.4xc2x0xc2x10.2xc2x0, 18.5xc2x0xc2x10.2xc2x0, 20.5xc2x0xc2x10.2xc2x0, 22.2xc2x0xc2x10.2xc2x0, 25.3xc2x0xc2x10.2xc2x0, 26.8xc2x0xc2x10.2xc2x0 and 27.8xc2x0xc2x10.2xc2x0 in a powder X-ray diffraction pattern.